Patterns of acute oncology admissions: an exploratory analysis of over 7000 patient episodes.

BACKGROUND: Following the National Chemotherapy Advisory Group report, calling for better management of patients with cancer admitted acutely to hospital, Clatterbridge Cancer Centre, with Merseyside and Cheshire Cancer Network, implemented an acute oncology service (AOS) for the region's seven acute trusts. STUDY DESIGN: We prospectively collected data on all referrals from March 2010 to December 2012, seen by the seven local teams within the cancer network. RESULTS: Over 7000 patient-episodes were analyzed. We found an AOS has the greatest impact on reducing hospital stay of patients admitted with complications of cancer treatment, compared with patients presenting with cancer symptoms, or those presenting with a new cancer as an emergency. Also an AOS significantly reduces the mortality rate of patients admitted with complications of cancer treatment, compared with patients presenting with cancer symptoms, either of a known cancer or those patients presenting with a new cancer as an emergency. CONCLUSIONS: Our network establishment of an AOS has had a positive impact on the quality of care cancer patients receive, in addition to saving local trusts valuable bed days, due to the overall reduction in hospital stay. This study also highlights deficiencies in the cancer journeys of certain patients with cancer, such as patients who present with a new cancer as an emergency admission, or patients unable to be discharged due to a lack of community resources. Such analysis is important in highlighting where the AOS can concentrate resources and collaborate with other healthcare professionals, especially within the local community.

Potential anticancer properties of bisphosphonates.

Bisphosphonates inhibit osteoclast-mediated bone resorption, which is increased when cancer cells invade bone, and are used in the treatment of metastatic bone disease to reduce the risk of skeletal-related events. In addition, preclinical studies have shown that bisphosphonates, especially potent nitrogen-containing bisphosphonates, have direct anticancer actions. Anticancer activity includes induction of apoptosis, and inhibition of invasion, in addition to synergistic activity with chemotherapy agents, antiangiogenic properties, and modulating effects on the immune system. In terms of potential clinical anticancer activity, early data suggest that zoledronic acid may have a role to play in preventing metastatic disease. The definitive answer is not known as yet; however, with more than 20,000 patients with breast, prostate, or lung cancer currently participating in adjuvant bisphosphonate randomized trials, results should be available in the next few years. This will establish whether bisphosphonates given early in the course of cancer will be able to prevent formation of metastases, in or out of the bone environment. This review will focus on emerging evidence of the anticancer activities of bisphosphonates and possible underlying mechanisms of action.

Osteoprotegerin (OPG)--a potential new role in the regulation of endothelial cell phenotype and tumour angiogenesis?

The progression of cancer depends on the establishment of a tumour blood supply, and therefore tumour angiogenesis has been identified as a major target for new anticancer agents. Recent reports have suggested that osteoprotegerin (OPG) is involved in the control of endothelial cell survival through the inhibition of the activity of tumour necrosis factor- (TNF) related apoptosis-inducing ligand (TRAIL). The role of OPG in human tumour development and angiogenesis is currently unknown. In the present study we demonstrate the ability of OPG to support endothelial cell survival, as well as the formation of cord-like structures in vitro using a matrigel tubule formation assay. Investigation of various human cancers demonstrated endothelial OPG expression in 59% of malignant tumours (n=512), but in contrast, OPG was absent in endothelial cells associated with benign tumours and normal tissues (n=178). In a series of 400 breast tumours, endothelial OPG expression was associated with high tumour grade and certain histological types. Our data show a clear separation in endothelial OPG expression between malignant tumours and nonmalignant tissues, supporting a potential biological role for this molecule in the development and/or maintenance of the tumour vasculature. This is the first study to report the proangiogenic effects of OPG in vitro, as well as correlating expression of OPG by tumour endothelial cells with clinicopathological data in human tumours.

Osteoprotegerin (OPG) expression by breast cancer cells in vitro and breast tumours in vivo--a role in tumour cell survival?

In addition to its role in bone turnover, osteoprotegerin (OPG) has been reported to bind to and inhibit Tumour necrosis factor-related apoptosis inducing ligand (TRAIL). TRAIL is produced in tumours by invading monocytes, inducing apoptosis in neoplastic cells sensitive to this cytokine. OPG production by tumour cells would therefore be a novel mechanism whereby cancer cells evade host defences and gain a growth advantage. In this study we show that OPG produced by breast cancer cells enhances tumour cell survival by inhibiting TRAIL-induced apoptosis. OPG expression by breast cancer cells (MDA-MB 436/231) grown in vitro was examined using PCR and ELISA, and the sensitivity of these cells to TRAIL was determined. The effects of OPG on TRAIL induced apoptosis was investigated by exposing MDA-MB 436 cells to TRAIL, in the presence or absence of OPG, followed by assessment of nuclear morphology. We found that the levels of OPG produced were sufficient to inhibit TRAIL-induced apoptosis, suggesting that OPG may play a role in tumour cell survival. We also examined the expression pattern of OPG in a selection of breast tumours (n=400) by immunohistochemistry, and related OPG expression to the clinico-pathological data for each tumour. OPG expression was found to be negatively correlated with increasing tumour grade. To our knowledge these results are the first to demonstrate that OPG can act as an endocrine survival factor for breast cancer cells, as well as reporting the expression patterns of OPG in a large cohort of human breast tumours.

Combined effects of zoledronic acid and doxorubicin on breast cancer cell invasion in vitro.

The bisphosphonate zoledronic acid and the cytotoxic drug doxorubicin induce synergistic levels of apoptosis in breast cancer cells. As zoledronic acid and doxorubicin have been shown to reduce cell invasion and migration, we have investigated if these drugs also act synergistically on breast cancer invasion in vitro. MCF7 cells were treated with 0.05 microM doxorubicin/4 h followed by 1 or 10 microM zoledronic acid/24 h (or the reverse sequence). To study invasion, MCF7 cells were either grown on Transwell membranes coated with Matrigel or in a 24-well plate. Cells were treated sequentially using the above drug combinations, prior to starting the invasion assays for 48 h. Cell growth and death were also assessed under the same conditions. We found that invasion of MCF7 cells treated with zoledronic acid and doxorubicin was significantly reduced when compared with control, but the effect was dependent on drug sequence. At 1 microM, zoledronic acid significantly reduced invasion only if cells were pre-treated with doxorubicin, but cell growth was unaffected. For 10 microM zoledronic acid, invasion was reduced when administered before or after the doxorubicin, but this dose of zoledronic acid caused a significant reduction in MCF7 growth. Apoptosis was not induced by any of the drug doses and combinations. We conclude that pre-treatment with 0.05 microM doxorubicin followed by 1 microM zoledronic acid reduces invasion when cells were grown on Matrigel. For 10 microM zoledronic acid, pre- or post-doxorubicin also reduces invasion, but for this combination inhibition of cell growth may contribute to the reduction in invasion observed.

Sequence- and schedule-dependent enhancement of zoledronic acid induced apoptosis by doxorubicin in breast and prostate cancer cells.

We investigated whether the combination of zoledronic acid and doxorubicin induced apoptosis of breast and prostate cancer cell lines, and if synergistic interaction was present. We investigated whether the levels of cell death altered depending on the sequence in which the drugs were administered and the possible mechanism of action responsible for the increased cell death following combined treatments. Breast and prostate cancer cells were treated with zoledronic acid alone, doxorubicin alone, or drugs in sequence (doxorubicin before, after, or with zoledronic acid), and the levels of apoptotic death were determined by evaluation of nuclear morphology. We found that clinically relevant concentrations of doxorubicin and zoledronic acid induced sequence- and schedule-dependent apoptosis of breast and prostate cancer cells. For maximal apoptosis, cells had to be pretreated for 24 hr with doxorubicin before immediate treatment with zoledronic acid for 1 hr. This observation is a characteristic feature of cell cycle phase-specific synergistic effect. Replacing zoledronic acid with the nonnitrogen-containing bisphosphonate clodronate did not induce increased apoptosis. Induction of apoptosis was mainly via inhibition of the mevalonate (MVA) pathway, as addition of the MVA pathway intermediary geranylgeraniol inhibited the induction of apoptosis by doxorubicin followed by zoledronic acid. In conclusion, combined treatment of breast and prostate cancer cell lines with clinically relevant doses of doxorubicin and zoledronic acid induces apoptosis in a synergistic fashion. These findings may have relevance for the clinical setting, particularly breast cancer patients receiving these drugs in the adjuvant setting.